Abstract LSUHSC CARC Research Component 2: Alcohol and Metabolic Dysregulation in PLWH: Mechanisms Underlying Risk for Comorbidities Reduced mortality rates with antiretroviral therapy (ART) and increased survival of persons living with human immunodeficiency virus (HIV) (PLWH), transformed HIV infection into a chronic disease that frequently coexists with at-risk alcohol drinking. Increased longevity of PLWH is complicated with comorbidities that may be exacerbated by at-risk alcohol consumption, unhealthy dietary behaviors, and ART adverse effects. Compromised metabolic health is directly linked to greater risk for comorbidities afflicting PLWH and increases progressively with time on ART. Data from our translational New Orleans Alcohol and HIV (NOAH) longitudinal study of in-care PLWH show high prevalence of overweight, obesity, at-risk alcohol use, and poor dietary habits. Subjects with at-risk alcohol use show greater incidence of impaired oral glucose tolerance. In addition, data from chronic binge alcohol administered ART-treated simian immunodeficiency virus-infected nonhuman primates (NHP) identified significant alterations in control (pancreas), effector (liver and adipose), and target (muscle and bone) organ metabolic homeostatic mechanisms associated with impaired response to glucose tolerance like that seen in the clinical setting. Collectively, published and preliminary clinical and preclinical data collected by our team of investigators support the scientific premise that alcohol-induced early intestinal pathogenesis promotes gut leak and immune activation promoting cellular energy metabolism dyshomeostasis. We hypothesize metabolic dyshomeostasis underlies the increased risk for comorbidities in PLWH. Studies proposed use a bidirectional translational approach to examine the mechanisms leading to metabolic instability and how this is affected by at-risk alcohol consumption and consumption of a Western diet. The proposed approach uses state-of-the-art techniques, combines in vivo with in vitro studies, and leverages our established NHP model of HIV infection and the parallel NOAH clinical longitudinal study to examine the mechanisms disrupted by alcohol in organs vital to the metabolic homeostatic axis in a virally-suppressed host. The expected results will have a profound impact on identification of the underlying mechanisms of alcohol-associated metabolic instability and will identify relevant targets for therapeutic interventions to ameliorate HIV/ART associated metabolic derangements.